Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-Dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)

ABSTRACT

Novel forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt designated Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, and Form XXX, characterized by their X-ray powder diffraction, solid-state NMR, and/or Raman spectroscopy are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as agents for treating hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer&#39;s disease.

This application is a divisional application of U.S. Ser. No. 13/214,559filed Aug. 22, 2011, now pending which is a divisional application ofU.S. Ser. No. 11/572,333 filed on Aug. 19, 2008, now U.S. Pat. No.8,026,376 which is a 371 application of PCT/1B2005/002181 filed on Jul.11, 2005, which claims benefit of provisional application U.S. Ser. No.60/589,485 filed on Jul. 20, 2004, all of which are incorporated hereinby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel forms of atorvastatin calciumwhich is known by the chemical name[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt useful as pharmaceutical agents, to methods fortheir production and isolation, to pharmaceutical compositions whichinclude these compounds and a pharmaceutically acceptable carrier, aswell as methods of using such compositions to treat subjects, includinghuman subjects, suffering from hyperlipidemia, hypercholesterolemia,osteoporosis, benign prostatic hyperplasia, and Alzheimer's disease.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which isincorporated herein by reference, is currently sold as Lipitor® havingthe chemical name[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate and the formula

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoAreductase. As such, atorvastatin calcium is a potent lipid loweringcompound and is thus useful as a hypolipidemic and/orhypocholesterolemic agent.

A number of patents have issued disclosing atorvastatin, formulations ofatorvastatin, as well as processes and key intermediates for preparingatorvastatin. These include: U.S. Pat. Nos. 4,681,893; 5,273,995;5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251;5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952;5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488;5,686,104; 5,998,633; 6,087,511; 6,126,971; 6,433,213; and 6,476,235,which are herein incorporated by reference.

Additionally, a number of published International Patent Applicationsand patents have disclosed crystalline forms of atorvastatin, as well asprocesses for preparing amorphous atorvastatin. These include: U.S. Pat.No. 5,969,156; U.S. Pat. No. 6,121,461;U.S. Pat. No. 6,605,729; WO00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO02/057274; WO 02/059087; WO 02/072073; WO 02/083637; WO 02/083638; WO03/050085; WO 03/070702; and WO 04/022053.

Atorvastatin is prepared as its calcium salt, i.e.,[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1). The calcium salt is desirable, since it enablesatorvastatin to be conveniently formulated in, for example, tablets,capsules, lozenges, powders, and the like for oral administration.

The process by which atorvastatin calcium is produced needs to be onewhich is amenable to large-scale production. Additionally, it isdesirable that the product should be in a form that is readilyfilterable and easily dried. Finally, it is economically desirable thatthe product be stable for extended periods of time without the need forspecialized storage conditions.

Furthermore, it has been disclosed that the amorphous forms in a numberof drugs exhibit different dissolution characteristics, and in somecases different bioavailability patterns compared to the crystallineforms (Konno T., Chem. Pharm. Bull., 1990; 38; 2003-2007). For sometherapeutic indications, one bioavailability pattern may be favored overanother.

In the course of drug development, it is generally assumed to beimportant to discover the most stable crystalline form of the drug. Thismost stable crystalline form is the form which is likely to have thebest chemical stability, and thus the longest shelf-life in aformulation. However, it is also advantageous to have multiple forms ofa drug, e.g. salts, hydrates, polymorphs, crystalline, andnoncrystalline forms. There is no one ideal physical form of a drugbecause different physical forms provide different advantages. Thesearch for the most stable form and for such other forms is arduous andthe outcome is unpredictable.

The successful development of a drug requires that it meet certainrequirements to be a therapeutically effective treatment for patients.These requirements fall into two categories: (1) requirements forsuccessful manufacture of dosage forms, and (2) requirements forsuccessful drug delivery and disposition after the drug formulation hasbeen administered to the patient.

There are many kinds of drug formulations for administration by variousroutes, and the optimum drug form for different formulations is likelyto be different. As mentioned above, a drug formulation must havesufficient shelf-life to allow successful distribution to patients inneed of treatment. In addition, a drug formulation must provide the drugin a form which will dissolve in the patient's gastrointestinal tractwhen orally dosed. For oral dosing in an immediate release dosage form,such as an immediate release tablet, capsule, suspension, or sachet, itis generally desirable to have a drug salt or drug form which has highsolubility, in order to assure complete dissolution of the dose andoptimal bioavailability. For some drugs, particularly low solubilitydrugs or poorly wetting drugs, it may be advantageous to utilize anoncrystalline drug form, which will generally have a higher initialsolubility than a crystalline form when administered into thegastrointestinal tract. A noncrystalline form of a drug is frequentlyless chemically stable than a crystalline form. Thus, it is advantageousto identify noncrystalline drug forms which are sufficiently chemicallystable to provide a practical product which is stable enough to maintainits potency for enough time to permit dosage form manufacture,packaging, storage, and distribution to patients around the world.

On the other hand, there are dosage forms which operate better if thedrug form is less soluble. For example, a chewable tablet or asuspension or a sachet dosage form exposes the tongue to the drugdirectly. For such dosage forms, it is desirable to minimize thesolubility of the drug in the mouth, in order to keep a portion of thedrug in the solid state, minimizing bad taste. For such dosage forms, itis often desirable to use a low solubility salt or crystalline form.

For controlled release oral or injectable, e.g. subcutaneous orintramuscular, dosage forms, the desired drug solubility is a complexfunction of delivery route, dose, dosage form design, and desiredduration of release. For a drug which has high solubility, it may bedesirable to utilize a lower solubility crystalline salt or polymorphfor a controlled release dosage form, to aid in achievement of slowrelease through slow dissolution. For a drug which has low solubility,it may be necessary to utilize a higher solubility crystalline salt orpolymorph, or a noncrystalline form, in order to achieve a sufficientdissolution rate to support the desired drug release rate from thecontrolled release dosage form.

In soft gelatin capsule dosage forms (“soft-gels”), the drug isdissolved in a small quantity of a solvent or vehicle such as atriglyceride oil or polyethylene glycol, and encapsulated in a gelatincapsule. An optimal drug form for this dosage form is one which has ahigh solubility in an appropriate soft-gel vehicle. In general, a drugform which is more soluble in a triglyceride oil will be less soluble inwater. Identification of an appropriate drug form for a soft-gel dosageform requires study of various salts, polymorphs, crystalline, andnoncrystalline forms.

Thus, it can be seen that the desired solubility of a drug form dependson the intended use, and not all drug forms are equivalent.

For a drug form to be practically useful for human or animal therapy, itis desirable that the drug form exhibit minimal hygroscopicity. Dosageforms containing highly hygroscopic drugs require protective packaging,and may exhibit altered dissolution if stored in a humid environment.Thus, it is desirable to identify nonhygroscopic crystalline salts andpolymorphs of a drug. If a drug is noncrystalline, or if anoncrystalline form is desired to improve solubility and dissolutionrate, then it is desirable to identify a noncrystalline salt or formwhich has a low hygroscopicity relative to other noncrystalline salts orforms.

A drug, crystalline or noncrystalline, may exist in an anhydrous form,or as a hydrate or solvate or hydrate/solvate. The hydration state andsolvation state of a drug affects its solubility and dissolutionbehavior.

The melting point of a drug may vary for different salts, polymorphs,crystalline, and noncrystalline forms. In order to permit manufacture oftablets on commercial tablet presses, it is desirable that the drugmelting point be greater than around 60° C., preferably greater than100° C. to prevent drug melting during tablet manufacture. A preferreddrug form in this instance is one that has the highest melting point. Inaddition, it is desirable to have a high melting point to assurechemical stability of a solid drug in a solid dosage form at highenvironmental storage temperatures which occur in direct sunlight and ingeographic areas such as near the equator. If a soft-gel dosage form isdesired, it is preferred to have a drug form which has a low meltingpoint, to minimize crystallization of the drug in the dosage form. Thus,it can be seen that the desired melting point of a drug form depends onthe intended use, and not all drug forms are equivalent.

When a drug's dose is high, or if a small dosage form is desired, theselection of a salt, hydrate, or solvate affects the potency per unitweight. For example, a drug salt with a higher molecular weightcounterion will have a lower drug potency per gram than will a drug saltwith a lower molecular weight counterion. It is desirable to choose adrug form which has the highest potency per unit weight.

The method of preparation of different crystalline polymorphs andnoncrystalline forms varies widely from drug to drug. It is desirablethat minimally toxic solvents be used in these methods, particularly forthe last synthetic step, and particularly if the drug has a tendency toexist as a solvate with the solvent utilized in the last step ofsynthesis. Preferred drug forms are those which utilize less toxicsolvents in their synthesis.

The ability of a drug to form good tablets at commercial scale dependsupon a variety of drug physical properties, such as the TabletingIndices described in Hiestand H, Smith D. Indices of tabletingperformance. Powder Technology, 1984; 38:145-159. These indices may beused to identify forms of a drug, e.g. of atorvastatin calcium, whichhave superior tableting performance. One such index is the BrittleFracture Index (BFI), which reflects brittleness, and ranges from 0(good-low brittleness) to 1 (poor-high brittleness). Other usefulindices or measures of mechanical properties, flow properties, andtableting performance include compression stress, absolute density,solid fraction, dynamic indentation hardness, ductility, elasticmodulus, reduced elastic modulus, quasistatic indentation hardness,shear modulus, tensile strength, compromised tensile strength, best casebonding index, worst case bonding index, brittle/viscoelastic bondingindex, strain index, viscoelastic number, effective angle of internalfriction (from a shear cell test), cohesivity (from a powder avalanchetest), and flow variability. A number of these measures are obtained ondrug compacts, preferably prepared using a triaxial hydraulic press.Many of these measures are further described in Hancock B, Carlson G,Ladipo D, Langdon B, and Mullarney M. Comparison of the MechanicalProperties of the Crystalline and Amorphous Forms of a Drug Substance.International Journal of Pharmaceutics, 2002; 241:73-85.

Drug form properties which affect flow are important not just for tabletdosage form manufacture, but also for manufacture of capsules,suspensions, and sachets.

The particle size distribution of a drug powder can also have largeeffects on manufacturing processes, particularly through effects onpowder flow. Different drug forms have different characteristic particlesize distributions.

From the above discussion, it is apparent that there is no one drug formwhich is ideal for all therapeutic applications. Thus it is important toseek a variety of unique drug forms, e.g. salts, polymorphs,noncrystalline forms, which may be used in various formulations. Theselection of a drug form for a specific formulation or therapeuticapplication requires consideration of a variety of properties, asdescribed above, and the best form for a particular application may beone which has one specific important good property while otherproperties may be acceptable or marginally acceptable.

We have now surprisingly and unexpectedly found novel forms ofatorvastatin calcium. Thus the present invention provides new forms ofatorvastatin calcium designated Forms XX, XXI, XXII, XXIII, XXIV, XXV,XXVI, XXVII, XXVIII, XXIX, XXX. The new forms of atorvastatin are purer,more stable, or have advantageous manufacturing and/or physicalproperties compared to forms of atorvastatin previously described.

In general, the new forms of atorvastatin calcium disclosed in thepresent application have high water solubility and high dissolutionrates. This is an advantage for immediate release dosage forms sincesuch forms need to be fully dissolved in the stomach before passing intothe digestive tract. Additionally, some of the new forms can be preparedusing solvents which are nontoxic. This avoids any residual solvents andtheir toxicity. Furthermore, some of the new forms have lowhygroscopicity which, as explained above, is desirable from a packagingor handling aspect. Also, some of the new forms have advantageoustableting properties and can be conveniently made into a tablet.Additionally, some of the new forms can be easily and directly prepared,which provide a cost advantage. Also, some of the new forms arephysically stable and not easily converted into other forms.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to Form XX atorvastatincalcium characterized by the following x-ray powder diffraction (XRPD)pattern expressed in terms of degree 28 and relative intensities with arelative intensity of >10% and relative peak width measured on aShimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 7.5-9.0 m vb17.5-26.0 s vb ^(a)s = strong; m = medium ^(b)vb = very broad (>1degrees 2θ peak width)

In a second aspect, the present invention is directed to Form XXIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 28 and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.1 w b 4.1 w b5.0 w b 6.3 w b 7.6 s b 8.6 m b, sh 9.2 w b, sh 10.1 w b 12.2 w b 16.7 mvb 18.2 m vb 19.2 m vb 20.1 m vb 20.5 w vb 23.1 m vb, sh 29.6 w vb ^(a)s= strong; m = medium; w = weak ^(b)b = broad, sh = shoulder, vb = verybroad (>1 degrees 2θ peak width)

In a third aspect, the present invention is directed to Form XXIIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 4.0 m b 4.9 w b8.0 m b 10.0 s b 11.1 w b 11.7 w b 12.2 w b 13.1 w b, sh 13.5 m b 14.0 wb 14.8 w b, sh 16.1 m b 16.4 m b, sh 17.0 m b 17.4 m b, sh 17.7 m b, sh19.2 w b 20.0 m b 20.3 m b 21.3 w b 22.6 w b 24.5 w vb 27.0 w b 28.1 w b28.9 w vb 29.4 w vb ^(a)s = strong; m = medium; w = weak ^(b)b = broad,sh = shoulder, vb = very broad (>1 degrees 2θ peak width)

In a fourth aspect, the present invention is directed to Form XXIIIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 29 and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.2 w b 4.1 w b5.0 w b 6.3 w b 7.2 w b, sh 7.7 s b 8.1 m b 8.5 m b 9.1 w b 10.1 w b10.5 w b 12.1 w b 12.8 w b 13.3 w b 16.7 m vb 18.4 m vb 19.1 m b 20.2 mvb 21.0 w b 21.4 m b 23.2 m vb 24.3 w b 25.2 w b 29.3 w b ^(a)s =strong; m = medium; w = weak ^(b)b = broad, sh = shoulder, vb = verybroad (>1 degrees 2θ peak width)

In a fifth aspect, the present invention is directed to Form XXIVatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 2.9 m b 4.6 w b5.2 w b 7.4 m b, sh 7.8 s b 8.7 m b 9.5 s b 10.0 w b 12.2 w vb 12.5 w b13.4 w b 13.9 w b 17.3 w vb 18.0 m b 18.6 m b 19.0 m b 20.6 w b 21.2 wvb 22.3 w vb 22.7 s b 23.2 m b, sh 24.2 w b 24.5 w vb 25.0 w vb 26.4 wvb 28.8 w vb 31.8 w b ^(a)s = strong; m = medium; w = weak ^(b)b =broad, sh = shoulder, vb = very broad (>1 degrees 2θ peak width)

In a sixth aspect, the present invention is directed to Form XXVatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.1 w b 5.2 wvb 6.4 w sh, b 7.4 s vb 7.9 w sh, vb 8.7 m vb 10.4 w vb 12.0 w vb 12.7 wvb 16.6 m vb 18.1 m vb 19.2 m vb 20.0 m b 20.7 m b 22.8 m vb 23.2 m vb24.4 m vb 25.6 w vb 26.5 w vb 29.3 w vb ^(a)s = strong; m = medium; w =weak ^(b)b = broad, sh = shoulder, vb = very broad (>1 degrees 2θ peakwidth)

In a seventh aspect, the present invention is directed to Form XXVIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.7 w b 7.3 wb, sh 8.4 s b 9.0 s b 12.2 w b 16.0 w vb 17.1 m vb 17.7 m vb 18.7 m b20.1 s b 20.7 m b, sh 22.3 m vb 23.0 m vb 25.2 m vb 28.7 w vb ^(a)s =strong; m = medium; w = weak ^(b)b = broad, sh = shoulder, vb = verybroad (>1 degrees 2θ peak width)

In an eighth aspect, the present invention is directed to Form XXVIIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.5 w b, sh 3.9m b 4.6 w b 7.1 w vb, sh 7.5 s b 7.9 m vb, sh 9.6 m b 9.9 m b 10.6 w b11.8 w b 13.0 w vb 15.3 w b 16.6 w vb 17.2 w vb 18.7 s b 22.6 w vb 23.8w b 25.1 w b ^(a)s = strong; m = medium; w = weak ^(b)b = broad, sh =shoulder, vb = very broad (>1 degrees 2θ peak width)

In an ninth aspect, the present invention is directed to Form XXVIIIatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Bruker diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 7.6 s b 9.5 m b12.2 w b 16.5 m b 17.0 m b 18.0 w b 19.2 w b 19.5 w b, sh 20.5 m b 20.9w b 21.5 w b 21.8 w b, sh 22.3 m vb 23.3 w b 23.8 w b ^(a)s = strong; m= medium; w = weak ^(b)b = broad, sh = shoulder, vb = very broad (>1degrees 2θ peak width)

In a tenth aspect, the present invention is directed to Form XXIXatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Bruker diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 8.0 m b 10.2 wb 11.5 m b 14.5 w b 15.3 w b 16.2 m vb 18.0 m b 19.6 m b 20.2 m b 20.6 wb 21.4 w b 22.3 m b 23.0 m b 23.9 w b 24.2 m b 24.9 s b 25.9 w vb 26.9 wb 28.6 w b 29.1 w b 30.4 w b 30.9 w b ^(a)s = strong; m = medium; w =weak ^(b)b = broad, sh = shoulder, vb = very broad (>1 degrees 2θ peakwidth)

In an eleventh aspect, the present invention is directed to Form XXXatorvastatin calcium characterized by the following x-ray powderdiffraction (XRPD) pattern expressed in terms of degree 2θ and relativeintensities with a relative intensity of >10% and relative peak widthmeasured on a Shimadzu diffractometer with CuK_(a) radiation:

Relative Relative degree 2θ Intensity^(a) Peak Width^(b) 3.1 s b 9.0 m b9.7 w b 10.5 w b 12.0 w b 16.5 w b 17.0 m b 19.0 m b 19.3 w b, sh 19.9 wb 20.9 m b 21.1 w b 21.6 s b 22.5 m vb 24.3 m b 26.7 w b 27.0 w b 27.6 wb 29.6 w b 31.8 w b ^(a)s = strong; m = medium; w = weak ^(b)b = broad,sh = shoulder, vb = very broad (>1 degrees 2θ peak width)

As inhibitors of HMG-CoA reductase, the novel forms of atorvastatincalcium are useful as hypolipidemic and hypocholesterolemic agents aswell as agents in the treatment of osteoporosis, benign prostatichyperplasia (BPH), and Alzheimer's disease.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of Form XX, Form XXI,Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, FormXXVIII, Form XXIX, or Form XXX atorvastatin calcium in unit dosage formin the treatment methods mentioned above. Finally, the present inventionis directed to methods for production of Form XX, Form XXI, Form XXII,Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII,Form XXIX, or Form XXX atorvastatin calcium.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further described by the following nonlimiting exampleswhich refer to the accompanying Forms XX, XXI, XXII, XXIII, XXIV, XXV,XXVI, XXVII, XXVIII, XXIX, and XXX, short particulars of which are givenbelow.

FIG. 1

Diffractogram of Form XX atorvastatin calcium carried out on a ShimadzuXRD-6000 diffractometer.

FIG. 2

Diffractogram of Form XXI atorvastatin calcium carried out on a ShimadzuXRD-6000 diffractometer.

FIG. 3

Diffractogram of Form XXII atorvastatin calcium carried out on aShimadzu XRD-6000 diffractometer.

FIG. 4

Diffractogram of Form XXIII atorvastatin calcium carried out on aShimadzu XRD-6000 diffractometer.

FIG. 5

Diffractogram of Form XXIV atorvastatin calcium carried out on aShimadzu XRD-6000 diffractometer.

FIG. 6

Diffractogram of Form XXV atorvastatin calcium carried out on a ShimadzuXRD-6000 diffractometer.

FIG. 7

Diffractogram of Form XXVI atorvastatin calcium carried out on aShimadzu XRD-6000 diffractometer.

FIG. 8

Diffractogram of Form XXVII atorvastatin calcium carried out on aShimadzu XRD-6000 diffractometer.

FIG. 9

Diffractogram of Form XXVIII atorvastatin calcium carried out on aBruker diffractometer.

FIG. 10

Diffractogram of Form XXIX atorvastatin calcium carried out on a Brukerdiffractometer.

FIG. 11

Diffractogram of Form XXX atorvastatin calcium carried out on a ShimadzuXRD-6000 diffractometer.

FIG. 12

Small angle diffractogram of Form XX atorvastatin calcium.

FIG. 13

Small angle diffractogram of Form XXII atorvastatin calcium.

FIG. 14

Small angle diffractogram of Form XXIV atorvastatin calcium.

FIG. 15

Small angle diffractogram of Form XXV atorvastatin calcium.

FIG. 16

Small angle diffractogram of Form XXVII atorvastatin calcium.

FIG. 17

Small angle diffractogram of Form XXX atorvastatin calcium.

FIG. 18

Raman spectrum of Form XX atorvastatin calcium.

FIG. 19

Raman spectrum of Form XXII atorvastatin calcium.

FIG. 20

Raman spectrum of Form XXIV atorvastatin calcium.

FIG. 21

Raman spectrum of Form XXV atorvastatin calcium.

FIG. 22

Raman spectrum of Form XXVII atorvastatin calcium.

FIG. 23

Raman spectrum of Form XXVIII atorvastatin calcium.

FIG. 24

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXatorvastatin calcium.

FIG. 25

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXIIatorvastatin calcium.

FIG. 26

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXIVatorvastatin calcium.

FIG. 27

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXVatorvastatin calcium.

FIG. 28

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXVIIatorvastatin calcium.

FIG. 29

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXVIIIatorvastatin calcium.

FIG. 30

Solid state ¹³C nuclear magnetic resonance spectrum of Form XXXatorvastatin calcium.

FIG. 31

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXatorvastatin calcium.

FIG. 32

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXIIatorvastatin calcium.

FIG. 33

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXIVatorvastatin calcium.

FIG. 34

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXVatorvastatin calcium.

FIG. 35

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXVIIatorvastatin calcium.

FIG. 36

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXVIIIatorvastatin calcium.

FIG. 37

Solid state ¹⁹F nuclear magnetic resonance spectrum of Form XXXatorvastatin calcium.

DETAILED DESCRIPTION OF THE INVENTION

Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, FormXXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX atorvastatincalcium may be characterized by x-ray powder diffraction patterns, bytheir solid state nuclear magnetic resonance spectra (NMR), and/or theirRaman spectra.

The “forms” of atorvastatin calcium disclosed in the present inventionmay exist as disordered crystals, liquid crystals, plastic crystals,mesophases, and the like. Forms that are related through disorder willhave essentially the same major peak positions but the disorderingprocess will cause broadening of these peaks. For many of the weakerpeaks, the broadening may be so severe that they are no longer visibleabove the background. The peak broadening caused by disorder may inaddition cause errors in the location of the exact peak position.

X-RAY POWDER DIFFRACTION

Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, FormXXVI, Form XXVII, Form XXVIII, Form XXIX, and Form XXX atorvastatincalcium were characterized by their X-ray powder diffraction pattern.Thus, the X-ray powder diffraction patterns of Forms XX, XXI, XXII,XXIII, XXIV, XXV, XXVI, XXVII, and XXX were carried out on a ShimadzuXRD-6000 X-ray diffractometer using Cu K_(a) radiation. This instrumentis equipped with a fine focus X-ray tube. The tube voltage and amperagewere set to 40 kV and 40 mA, respectively. The divergence and scatteringslits were set at 1°, and the receiving slit was set at 0.15 mm.Diffraction radiation was detected by a NaI scintillation detector. Atheta-two theta continuous scan at 3° C./min (0.4 sec/0.02° step) from2.5 to 40 °2θ was used. A silicon standard was analyzed each day tocheck the instrument alignment. Data were collected and analyzed usingXRD-6000 V. 4.1. Samples were prepared for analysis by placing them inan aluminum holder.

The X-ray powder diffraction patterns of Forms XXVIII and XXIX werecarried out on a Bruker D5000 diffractometer using Cu K_(a) radiation.The instrument was equipped with a fine focus X-ray tube. The tubevoltage and amperage were set to 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 1 mm, and the receiving slitwas set at 0.6 mm. Diffracted radiation was detected by a Kevex PSIdetector. A theta two theta continuous scan at 2.4°/min (1 sec/0.04°step) from 3.0 to 40 °2θ was used. An alumina standard was analyzed tocheck the instrument alignment. Data were collected and analyzed usingBruker axs software Version 7.0. Samples were prepared for analysis byplacing them in a quartz holder. It should be noted that BrukerInstruments purchased Siemans; thus, a Bruker D5000 instrument isessentially the same as a Siemans D5000.

To perform an X-ray diffraction measurement on a Bragg-Brentanoinstrument like the Shimadzu system or the Bruker system used formeasurements reported herein, the sample is typically placed into aholder which has a cavity. The sample powder is pressed by a glass slideor equivalent to ensure a random surface and proper sample height. Thesample holder is then placed into the Shimadzu instrument. The incidentX-ray beam is directed at the sample, initially at a small anglerelative to the plane of the holder, and then moved through an arc thatcontinuously increases the angle between the incident beam and the planeof the holder. Measurement differences associated with such X-ray powderanalyses result from a variety of factors including: (a) errors insample preparation (e.g., sample height), (b) instrument errors (e.g.flat sample errors), (c) calibration errors, (d) operator errors(including those errors present when determining the peak locations),and (e) the nature of the material (e.g. preferred orientation andtransparency errors). Calibration errors and sample height errors oftenresult in a shift of all the peaks in the same direction. Smalldifferences in sample height when using a flat holder will lead to largedisplacements in XRPD peak positions. A systematic study showed that,using a Shimadzu XRD-6000 in the typical Bragg-Brentano configuration,sample height difference of 1 mm lead to peak shifts as high as 1 °2θ(Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001; 26,63).These shifts can be identified from the X-ray Diffractogram and can beeliminated by compensating for the shift (applying a systematiccorrection factor to all peak position values) or recalibrating theinstrument. As mentioned above, it is possible to rectify measurementsfrom the various machines by applying a systematic correction factor tobring the peak positions into agreement. In general, this correctionfactor will bring the measured peak positions from the Shimadzu or theBruker into agreement with the expected peak positions and may be in therange of 0 to 0.2 °2θ.

Tables 1-11 list peak positions in degrees 2θ, relative intensities, andrelative peak widths for X-ray powder diffraction patterns of each formof atorvastatin calcium disclosed in the present application. Therelatively narrow peak positions were picked by the Shimadzu softwareusing default settings. X-ray powder diffraction patterns were processedby the Shimadzu XRD-6000 version 2.6 software to automatically find peakpositions. The “peak position” means the maximum intensity of a peakedintensity profile. To maximize accuracy and precision, the entireintensity profile is considered when selecting peak positions. Intensityspikes from large crystals and the expected intensity fluctuations fromnoise were considered in picking the position of a peak.

The following processes were used with the Shimadzu XRD-6000 “BasicProcess” version 2.6 algorithm:

-   1. Smoothing was done on all patterns.-   2. The background was subtracted to find the net, relative intensity    of the peaks.-   3. A peak from CuK_(a) alpha2 (1.5444 Å) wavelength was subtracted    from the peak generated by CuK_(a) alpha1 (1.5406 Å) peak at 50%    intensity for all patterns.

Default values of the software were used in picking the peaks and allpeak positions were rounded to 1/10^(th). Some of the XRPD patternsdisplayed very diffuse and very noisy patterns and the peak positionswere determined manually, and expressed as a range of degree 2 theta(from the beginning of the broad peak to the end of the broad peak). Allpeak positions were rounded to 0.1 °2θ. The following abbreviations areused to describe the peak intensity (s=strong; m=medium; w=weak) and thepeak width (b=broad (where broad refers to peak widths of between 0.2and 1.0 degrees 2θ, sh=shoulder, vb=very broad (where very broad refersto peaks with >1 degrees 2θ peak width)).

TABLE 1 XPRD Peak List for Form XX Relative Relative degree 2θIntensity^(a) Peak Width^(b) 7.5-9.0 m vb 17.5-26.0 s vb ^(a)s = strong;m = medium; w = weak ^(b)b = broad; sh = shoulder; vb = very broad (>1degrees 2θ peak width)

TABLE 2 XPRD Peak List for Form XXI Relative Relative degree 2θIntensity^(a) Peak Width^(b) 3.1 w b 4.1 w b 5.0 w b 6.3 w b 7.6 s b 8.6m b, sh 9.2 w b, sh 10.1 w b 12.2 w b 16.7 m vb 18.2 m vb 19.2 m vb 20.1m vb 20.5 w vb 23.1 m vb, sh 29.6 w vb ^(a)s = strong; m = medium; w =weak ^(b)b = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peakwidth)

TABLE 3 XPRD Peak List for Form XXII degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 4.0 m b 4.9 w b 8.0 m b 10.0 s b 11.1 w b 11.7 wb 12.2 w b 13.1 w b, sh 13.5 m b 14.0 w b 14.8 w b, sh 16.1 m b 16.4 mb, sh 17.0 m b 17.4 m b, sh 17.7 m b, sh 19.2 w b 20.0 m b 20.3 m b 21.3w b 22.6 w b 24.5 w vb 27.0 w b 28.1 w b 28.9 w vb 29.4 w vb ^(a)s =strong; m = medium; w = weak ^(b)b = broad; sh = shoulder; vb = verybroad (>1 degrees 2θ peak width)

TABLE 4 XPRD Peak List for Form XXIII degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 3.2 w b 4.1 w b 5.0 w b 6.3 w b 7.2 w b, sh 7.7s b 8.1 m b 8.5 m b 9.1 w b 10.1 w b 10.5 w b 12.1 w b 12.8 w b 13.3 w b16.7 m vb 18.4 m vb 19.1 m b 20.2 m vb 21.0 w b 21.4 m b 23.2 m vb 24.3w b 25.2 w b 29.3 w b ^(a)s = strong; m = medium; w = weak ^(b)b =broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE 5 XPRD Peak List for Form XXIV degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 2.9 m b 4.6 w b 5.2 w b 7.4 m b, sh 7.8 s b 8.7m b 9.5 s b 10.0 w b 12.2 w vb 12.5 w b 13.4 w b 13.9 w b 17.3 w vb 18.0m b 18.6 m b 19.0 m vb 20.6 w b 21.2 w vb 22.3 w vb 22.7 s b 23.2 m b,sh 24.2 w b 24.5 w vb 25.0 w vb 26.4 w vb 28.8 w vb 31.8 w b ^(a)s =strong; m = medium; w = weak ^(b)b = broad; sh = shoulder; vb = verybroad (>1 degrees 2θ peak width)

TABLE 6 XPRD Peak List for Form XXV degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 3.1 w b 5.2 w vb 6.4 w sh, b 7.4 s vb 7.9 w sh,vb 8.7 m vb 10.4 w vb 12.0 w vb 12.7 w vb 16.6 m vb 18.1 m vb 19.2 m vb20.0 m b 20.7 m b 22.8 m vb 23.2 m vb 24.4 m vb 25.6 w vb 26.5 w vb 29.3w vb ^(a)s = strong; m = medium; w = weak ^(b)b = broad; sh = shoulder;vb = very broad (>1 degrees 2θ peak width)

TABLE 7 XPRD Peak List for Form XXVI degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 3.7 w b 7.3 w b, sh 8.4 s b 9.0 s b 12.2 w b16.0 w vb 17.1 m vb 17.7 m vb 18.7 m b 20.1 s b 20.7 m b, sh 22.3 m vb23.0 m vb 25.2 m vb 28.7 w vb ^(a)s = strong; m = medium; w = weak ^(b)b= broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE 8 XPRD Peak List for Form XXVII degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 3.5 w b, sh 3.9 m b 4.6 w b 7.1 w vb, sh 7.5 s b7.9 m vb, sh 9.6 m b 9.9 m b 10.6 w b 11.8 w b 13.0 w vb 15.3 w b 16.6 wvb 17.2 w b 18.7 s b 22.6 w vb 23.8 w b 25.1 w b ^(a)s = strong; m =medium; w = weak ^(b)b = broad; sh = shoulder; vb = very broad (>1degrees 2θ peak width)

TABLE 9 XPRD Peak List for Form XXVIII degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 7.6 s b 9.5 m b 12.2 w b 16.5 m b 17.0 m b 18.0w b 19.2 w b 19.5 w b, sh 20.5 m b 20.9 w b 21.5 w b 21.8 w b, sh 22.3 mvb 23.3 w b 23.8 w b ^(a)s = strong; m = medium; w = weak ^(b)b = broad;sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE 10 XPRD Peak List for Form XXIX degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 8.0 m b 10.2 w b 11.5 m b 14.5 w b 15.3 w b 16.2m vb 18.0 m b 19.6 m b 20.2 m b 20.6 w b 21.4 w b 22.3 m b 23.0 m b 23.9w b 24.2 m b 24.9 s b 25.9 w vb 26.9 w b 28.6 w b 29.1 w b 30.4 w b 30.9w b ^(a)s = strong; m = medium; w = weak ^(b)b = broad; sh = shoulder;vb = very broad (>1 degrees 2θ peak width)

TABLE 11 XPRD Peak List for Form XXX degree 2θ Relative Intensity^(a)Relative Peak Width^(b) 3.1 s b 9.0 m b 9.7 w b 10.5 w b 12.0 w b 16.5 wb 17.0 m b 19.0 m b 19.3 w b, sh 19.9 w b 20.9 m b 21.1 w b 21.6 s b22.5 m vb 24.3 m b 26.7 w b 27.0 w b 27.6 w b 29.6 w b 31.8 w b ^(a)s =strong; m = medium; w = weak ^(b)b = broad; sh = shoulder; vb = verybroad (>1 degrees 2θ peak width)

Table 12 lists combinations of 2θ peaks for Forms XXI, XXII, XXIII,XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium,i.e., a set of x-ray diffraction lines that are unique to each form.

TABLE 12 Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX,and XXX. degree Form 2θ XXI 3.1 4.1 5.0 7.6 16.7 18.2 19.2 20.1 20.523.1 XXII 4.0 8.0 10.0 13.5 16.1 16.4 17.0 17.4 19.2 20.0 20.3 XXIII 4.15.0 6.3 7.7 8.5 9.1 10.5 16.7 18.4 20.2 21.4 XXIV 2.9 7.4 7.8 8.7 9.510.0 12.2 18.0 18.6 19.0 22.7 XXV 3.1 5.2 7.4 8.7 10.4 12.7 16.6 18.119.2 20.0 20.7 23.2 24.4 XXVI 3.7 8.4 9.0 17.1 17.7 18.7 20.1 22.3 23.0XXVII 3.9 4.5 7.1 7.5 9.6 10.6 11.8 13.0 15.3 18.7 XXVIII 7.6 9.5 12.216.5 17.0 18.0 20.5 21.5 22.3 XXIX 8.0 10.2 11.5 14.5 15.3 18.0 19.620.2 22.3 24.9 XXX 3.1 9.0 9.7 12.0 16.5 17.0 20.9 21.6 22.5 24.3

Further, Table 13 lists additional combinations of 2θ peaks for FormsXXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXXatorvastatin calcium, i.e., an additional set of x-ray diffraction linesthat are unique to each form.

TABLE 13 Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII,XXIX, and XXX Degree Form 2θ Form XXI 3.1 4.1 5.0 7.6 16.7 18.2 19.223.1 Form XXII 4.0 10.0 13.5 17.0 19.2 20.3 Form XXIII 4.1 5.0 6.3 7.78.5 9.1 10.5 16.7 21.4 Form XXIV 2.9 7.4 7.8 8.7 9.5 12.2 18.6 19.0 22.7Form XXV 3.1 5.2 7.4 8.7 23.2 24.4 Form XXVI 3.7 8.4 9.0 17.1 18.7 20.123.0 Form XXVII 3.9 4.5 7.5 9.6 10.6 13.0 15.3 18.7 Form XXVIII 7.6 9.512.2 16.5 17.0 18.0 21.5 22.3 Form XXX 9.0 9.7 12.0 16.5 17.0 21.6 22.524.3

SMALL ANGLE POWDER X-RAY DIFFRACTION

Methodology

Powder materials of different lots of atorvastatin calcium were packedin either glass or quartz x-ray capillaries with diameter of 1 to 2 mm.Small-Angle X-Ray Diffraction (SAXD) experiments were performed at thebeamline ID2, European Synchrotron Radiation Facility (ESRF), Grenoble,France. The radiation wavelength was 0.996 Å (silicon channel-cutmonochromator). The 2-dimensional SAXD images were recorded usingimage-intensified charge coupled device (CCD) detector and the data wasexpressed as reciprocal spacing q in nm⁻¹ units. The exposure time wasadjusted to use the maximum dynamic of the detectors for everyparticular sample and was less than 1s in the majority of cases. The2-dimensional images were normalized to an absolute intensity scaleafter performing the standard detector corrections and azimuthallyintegrated to obtain the corresponding 1-dimensional x-ray diffractioncurves. Peaks positions were measured using Gaussian fit using singlepeak analysis. The SAXD and (wide angle x-ray diffraction) WAXD q-scaleswere calibrated with silver behenate and silicon powders, respectively.

Table 14 shows the SAXRD peaks for Forms XX, XXII, XXIV, XXV, XXVII andXXX atorvastatin calcium.

TABLE 14 SAXRD Data Form Position of peaks, q, nm⁻¹ XX 2.11 3.93 XXII2.85 3.48 4.16 XXIV 2.09 2.24 2.84 3.33 3.54 3.69 4.50 5.23 XXV 2.222.86 3.62 4.46 5.28 XXVII 2.19 2.76 2.86 3.27 3.33 4.00 4.69 4.97 XXX2.13 4.26

RAMAN SPECTROSCOPY

Methodology

The Raman spectrum was obtained on a Raman accessory interfaced to aNicolet Magna 860 Fourier transform infrared spectrometer. The accessoryutilizes an excitation wavelength of 1064 nm and approximately 0.45 W ofneodymium-doped yttrium aluminum garnet (Nd:YAG) laser power. Thespectrum represents 6 or 128 co-added scans acquired at 4 cm⁻¹resolution. The sample was prepared for analysis by placing a portioninto a 5-mm diameter glass tube and positioning this tube in thespectrometer. Peak tables were generated using the Nicolet software withdefault threshold and sensitivity settings. The spectrometer wascalibrated (wavelength) with sulfur and cyclohexane at the time of use.

Table 15 shows the Raman spectra for Forms XX, XXII, XXIV, XXV, XXVII,and XXVIII atorvastatin calcium.

TABLE 15 Raman Peak Listing Peak Positions in Wavenumbers (cm⁻¹) Formcm⁻¹ XX 618 818 855 892 999 1034 1158 1178 1244 1412 1480 1528 1558 16041649 3059 XXII 618 820 855 998 1033 1157 1243 1364 1410 1526 1603 16713059 XXIV 133 217 247 298 422 500 617 643 697 789 811 825 857 900 925961 1000 1034 1056 1112 1160 1179 1240 1301 1370 1398 1413 1473 15271603 1651 2263 2555 2922 2972 3062 XXV 138 224 245 300 422 495 617 644697 726 825 859 901 1001 1034 1058 1112 1159 1181 1243 1320 1368 13971412 1477 1528 1604 1654 2257 2933 3063 XXVII 130 288 366 512 581 618634 736 821 858 898 998 1034 1112 1158 1240 1314 1368 1411 1481 15271559 1578 1604 1658 2927 3063 XXVIII 148 248 296 341 405 522 478 617 642699 755 824 863 999 1034 1062 1090 1159 1180 1242 1298 1316 1369 14121468 1525 1603 1640 2882 2940 3060 3376

SOLID STATE NUCLEAR MAGNETIC RESONANCE (NMR)

Methodology

Solid-state ¹³C NMR and ¹⁹F NMR spectra were obtained at 293K on 500 MHzNMR spectrometer. Approximately 80 mg of sample were tightly packed intoa 4 mm ZrO spinner for analysis. The one-dimensional solid state spectrawere collected at ambient pressure and 293 K on a wide-boreBruker-Biospin Avance DSX 500 MHz NMR spectrometer using a Bruker 4 mmHFX BL cross-polarization magic angle spinning (CPMAS) probe. Tominimize the spinning side bands, spinning speed was set to 15.0 kHz,the maximum specified spinning speed for the 4 mm HFX BL probe. ¹³CCPMAS and ¹⁹F MAS peaks were peak-picked using Bruker-Biospin TOPSPIN1.3 software, by suitably setting the spectral window and the peakpicking threshold intensity to eliminate peak picking of spinning sidebands. The detection sensitivity parameter (PC) was typically set to0.5.

¹³C CPMAS

The one-dimensional ¹³C spectra were collected using ¹H-¹³Ccross-polarization magic angle spinning (CPMAS). To optimize the signalsensitivity, the cross-polarization contact time was adjusted to 2.3 ms,and the decoupling power was set to 80 kHz. The carbon spectra wereacquired with approximately 1,100 scans with a recycle delay of 8seconds. They were referenced using an external sample of adamantane,setting its upfield resonance to 29.5 ppm.

¹⁹F MAS

The one-dimensional ¹⁹F spectra were collected using magic anglespinning (MAS) with proton decoupling. The decoupling field was set toapproximately 65 kHz. ¹⁹F detected ¹H T1 relaxation times werecalculated based on inversion recovery experiments. For all samples, theprobe background was reduced by subtracting signal from interleavedscans, during which a ¹⁹F presaturation pulse was applied. The spectrawere acquired with approximately 64 scans with a recycle delay of 10seconds. The samples were referenced using an external sample oftrifluoroacetic acid (diluted to 50% V/V by H₂O), setting its resonanceto −76.54 ppm.

Table 16 shows the ¹³C solid state NMR spectrum for Forms XX, XXII,XXIV, XXV, XXVII, XXVIII, and XXX atorvastatin calcium. Table 17 showsthe ¹⁹F solid state NMR spectrum for Forms XX, XXII, XXIV, XXV, XXVII,XXVIII, and XXX atorvastatin calcium.

TABLE 16 CPMAS ¹³C Data Form Solid State Chemical Shift^(a) [ppm] XX180.7 166.8 162.9 161.0 134.7 128.5 122.5 118.6 69.8 41.8 26.1 21.7 XXII182.1 166.6 164.1 161.8 143.7 139.4 136.1 134.2 129.1 123.4 119.7 115.768.7 45.1 43.9 39.1 37.4 26.8 22.7 20.6 18.3 XXIV 187.5 185.2 184.2180.5 179.0 178.4 177.4 166.8 162.7 160.9 138.7 136.2 133.7 128.7 124.4122.4 121.2 120.5 118.0 115.7 69.8 67.4 65.7 46.4 44.3 43.5 40.6 26.725.5 21.8 19.6 0.0 XXV 186.3 185.0 182.5 177.0 167.0 166.2 162.8 160.9138.6 136.1 133.4 129.2 128.5 126.0 124.0 121.5 120.7 118.0 116.8 116.069.9 68.0 46.4 43.3 40.9 25.7 25.2 21.3 20.0 0.6 XXVII 179.7 166.0 163.6161.7 140.7 133.8 128.8 122.4 115.3 72.5 70.9 66.6 41.8 27.3 22.0 XXVIII184.1 183.4 181.2 180.9 166.8 162.5 160.5 138.1 137.5 135.3 134.5 132.8131.4 131.1 130.0 129.6 127.7 123.9 123.1 121.4 120.6 118.4 117.6 113.173.7 73.1 71.7 66.8 65.9 63.9 46.7 43.0 26.5 24.7 23.8 21.4 21.0 XXX181.0 177.2 167.2 162.5 160.5 137.8 137.1 135.4 134.4 132.3 131.2 129.9128.2 127.4 123.7 123.1 121.8 120.9 118.6 117.8 113.9 67.9 65.4 63.947.5 47.0 46.2 43.3 41.5 40.5 26.2 25.5 24.9 21.8 21.4 ^(a)Referencedusing an external standard of crystalline adamantane, setting itsupfield resonance to 29.5 ppm.

TABLE 17 MAS ¹⁹F Data Form Fluorine chemical shift^(a) [ppm] XX −113.9XXII −112.0 −114.8 −118.9 XXIV −114.0 −116.8 −117.9 XXV −113.2 −116.3−118.4 XXVII −112.2 −113.0 −117.2 XXVIII −116.4 −117.1 −119.2 XXX −116.7−118.6 ^(a)Referenced using an external sample of trifluoroacetic acid(diluted to 50% V/V by H₂O), setting its resonance to −76.54 ppm.

Additionally, Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII,XXIX, and XXX atorvastatin calcium may be characterized by an x-raypowder diffraction and a solid state ¹⁹F nuclear magnetic resonancespectrum. For example:

A Form XXII atorvastatin calcium having an x-ray powder diffractioncontaining the following 28 values measured using CuK_(a) radiation:10.0, 16.1, and 19.2, and a solid state ¹⁹F nuclear magnetic resonancehaving the following chemical shifts expressed in parts per million:−112.0, −114.8, and −118.9.

A Form XXIV atorvastatin calcium having an X-ray powder diffractioncontaining the following 28 values measured using CuK_(a) radiation:7.4, 9.5 and 12.2, and a solid state ¹⁹F nuclear magnetic resonancehaving the following chemical shifts expressed in parts per million:−114.0, −116.8, and −117.9.

A Form XXV atorvastatin calcium having an x-ray powder diffractioncontaining the following 2θ values measured using CuK_(a) radiation:7.4, 8.7, 19.2, and 20.0, and a solid state ¹⁹F nuclear magneticresonance having the following chemical shifts expressed in parts permillion: −113.2, −116.3, and −118.4.

A Form XXVII atorvastatin calcium having an x-ray powder diffractioncontaining the following 2θ values measured using CuK_(a) radiation:3.9, 7.5, and 18.7, and a solid state ¹⁹F nuclear magnetic resonancehaving the following chemical shifts expressed in parts per million:−112.2, −113.0, and −117.2.

A Form XXVIII atorvastatin calcium having an x-ray powder diffractioncontaining the following 2θ values measured using CuK_(a) radiation:7.6, 9.5, 20.5, and 22.3, and a solid state ¹⁹F nuclear magneticresonance having the following chemical shifts expressed in parts permillion: −116.4, −117.1, and −119.2.

A Form XXX atorvastatin calcium having an x-ray powder diffractioncontaining the following 2θ values measured using CuK_(a) radiation:3.1, 9.0, and 21.6, and a solid state ¹⁹F nuclear magnetic resonancehaving the following chemical shifts expressed in parts per million:−116.7 and −118.6.

The forms of atorvastatin calcium described in the present invention mayexist in anhydrous forms as well as containing various amounts of waterand/or solvents. In general, these forms are equivalent to the anhydrousforms and are intended to be encompassed within the scope of the presentinvention.

The forms of atorvastatin calcium of the present invention, regardlessof the extent of water and/or solvent having equivalent x-ray powderdiffractograms are within the scope of the present invention.

The new forms of atorvastatin calcium described in the presentapplication have advantageous properties.

The ability of a material to form good tablets at commercial scaledepends upon a variety of physical properties of the drug, such as, forexample, the Tableting Indices described in Hiestand H. and Smith D.,Indices of Tableting Performance, Powder Technology, 1984, 38; 145-159.These indices may be used to identify forms of atorvastatin calciumwhich have superior tableting performance. One such index is the BrittleFracture Index (BFI), which reflects brittleness, and ranges from 0(good-low brittleness) to 1 (poor-high brittleness).

The present invention provides a process for the preparation of FormsXX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXXatorvastatin calcium which comprises forming atorvastatin calcium from asolution or slurry in solvents under conditions which yield Forms XX,XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXXatorvastatin calcium.

The precise conditions under which Forms XX, XXI, XXII, XXIII, XXIV,XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium are formedmay be empirically determined, and it is only possible to give a numberof methods which have been found to be suitable in practice.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulation material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from two or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, methylcellulose, sodium carboxymethylcellulose, a low meltingwax, cocoa butter, and the like. The term ‘preparation’ is intended toinclude the formulation of the active compound with encapsulatingmaterial as a carrier providing a capsule in which the active component,with or without other carriers, is surrounded by a carrier, which isthus in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges canbe used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dosage preparation may bevaried or adjusted from 0.5 mg to 100 mg, preferably 2.5 to 80 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as hypolipidemic and/or hypocholesterolemic agentsand agents to treat BPH, osteoporosis, and Alzheimer's disease, theForms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, andXXX atorvastatin calcium utilized in the pharmaceutical method of thisinvention are administered at the initial dosage of about 2.5 mg toabout 80 mg daily. A daily dose range of about 2.5 mg to about 20 mg ispreferred. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention:

EXAMPLE 1[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt (Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI,XXVII, XXVIII, XXIX, and XXX atorvastatin calcium)

Form XX Atorvastatin Calcium

Method A

A 12.2 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156,which is herein incorporated by reference) was suspended in 300 mL ofmethanol (MeOH):H₂O (95:5, v:v) and sonicated. The resulting suspensionwas filtered into a 1 L flask. The sample was evaporated on a rotaryevaporator with an unheated water bath and the vacuum provided with anaspirator. The solid obtained was dried under vacuum at ambienttemperature overnight to afford Form XX atorvastatin calcium.

Method B

A 24 mg sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was dissolved in 7 mL of ethanol (EtOH):H₂O (4:1, v:v) and filteredthrough a 0.2 μm nylon filter. The resulting solution was evaporated inan open vial to dryness to afford Form XX atorvastatin calcium.

Form XXI Atorvastatin Calcium

Method A

A 3.6 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was dissolved in 10 mL of tetrahydrofuran:water (9:1, v/v) at 43° C. A1-mL aliquot was filtered into a vial and approximately 1 mL ofpre-warmed acetonitrile (ACN) was added drop-wise. The clear solutionwas placed in a refrigerator. Solids formed within 1 day, recovered withvacuum filtration, and air-dried at ambient temperature to afford FormXXI atorvastatin calcium.

Method B

A 10.5 g sample of Form I (U.S. Pat. No. 5,969,156) was slurried in 450mL of isopropyl alcohol (IPA)/50 mL H₂O (9:1) at room temperature for 20days. The sample was then vacuum filtered. The sample was then slurriedin 450 mL of ACN/50 mL H₂0 (9:1) overnight. The sample was vacuumfiltered for 5 hours to afford Form XXI atorvastatin calcium.

Form XXII Atorvastatin Calcium

An 11.5 g sample of Form XX atorvastatin calcium (prepared as describedabove) was mixed with 29 mL of MeOH and stirred on an ambienttemperature orbital shaker for 1 day. The sample was then vacuum driedat ambient temperature for 1 day. The recovered solid was mixed with 29mL of MeOH and slurried on an ambient temperature orbital shaker forless than 1 hour. The gel that formed was then mixed with an additional40 mL of MeOH and slurried on the ambient temperature orbital shaker for3 days. The solids were vacuum dried at ambient temperature for 1 day toafford Form XXII atorvastatin calcium.

Form XXIII Atorvastatin Calcium

Method A

A 1.5 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was slurried with approximately 75 mL of ACN:water (9:1, v/v) in a flaskand placed on an ambient temperature orbital shaker block for 1 day. Thesample was divided into four portions and centrifuged and thesupernatant decanted and discarded. The recovered solids were returnedto the shaker block for 1 hour. The samples were air dried for less than1 day. The four portions were recombined and the sample was furtherair-dried at ambient conditions for 3 hours to afford Form XXIIIatorvastatin calcium.

Method B

An 11.0 g sample of Form I atorvastatin calcium (U.S. Pat. No.5,969,156) was slurried with approximately 430 mL of ACN:water (9:1,v/v) on an ambient temperature magnetic stir plate at 500 rpm for 2days. The sample was vacuum filtered through a 0.22-μm nylon membranefilter and the filtered solids were air dried at ambient conditions for1 day to afford Form XXIII atorvastatin calcium.

Form XXIV Atorvastatin Calcium

A 1.0 g sample containing a mixture of amorphous atorvastatin calcium(U.S. Pat. No. 6,087,511, which is herein incorporated by reference) andForm XX atorvastatin calcium (prepared as described above) was slurriedwith 195 mL of ACN:water (9:1, v/v) in a flask and placed on a magneticstir plate set at 55° C. and 500 rpm for 1 day. The sample was vacuumfiltered using a 0.22-μm nylon membrane filter and the solids wereslurried with 195 mL of the fresh solvent at the same conditions for 1day. Again, the sample was vacuum filtered using 0.22-μm nylon membranefilter and the solids were slurried with 195 mL of the fresh solvent atthe same conditions for 1 day. The solids were isolated by vacuumfiltration and were air dried in a petri dish at ambient conditions for4 days to afford Form XXIV atorvastatin calcium.

Form XXV Atorvastatin Calcium

A 58 mg sample of Form XX atorvastatin calcium (prepared as describedabove) was slurried in 2 mL of ACN:water (9:1) on a magnetic stir platefor 5 days and then filtered to afford Form XXV atorvastatin calcium.

Form XXVI Atorvastatin Calcium

Method A

A 2.0 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was slurried with 0.57 mL of water in a vial, 5.1 mL of MeOH added, andthe sample was placed on an orbital shaker block at 58 to 60° C. for 3days. The resulting sample was vacuum dried between 70-75° C. for 3 daysto afford Form XXVI atorvastatin calcium.

Method B

A 5.0 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was dissolved in 200 mL of 80:20 (v/v) water/MeOH at 60° C. Afterforming a solution, a slurry resulted while stirring at 60° C. Theslurry was isolated via vacuum filtration after 2.5 hours. The materialwas vacuum dried at 45° C. overnight to afford Form XXVI atorvastatincalcium.

Form XXVII Atorvastatin Calcium

Method A

A sample of Form VIII atorvastatin calcium (U.S. Pat. No. 6,605,729,which is herein incorporated by reference) was heated on a sample holderin a Variable Temperature X-ray powder diffraction unit at 5° C./minuteramp rate. The temperature was held at 35°, 80°, 100°, 115°, and 140° C.for approximately 15 minutes before reaching 165° C. to afford FormXXVII atorvastatin calcium. The Form XXVII atorvastatin calcium remainedunchanged upon cooling to 40° C.

Method B

A sample of Form VIII atorvastatin calcium (U.S. Pat. No. 6,605,729) washeated using a variable temperature XRPD with humidity conditionsremaining uncontrolled throughout the experiment. The sample was heatedin a series of 4 steps beginning at 35° C. It continued up to 135° C.(holding for 13.5 min) and then on to 148° C. (holding for 15.5 min)before returning to 35° C. (holding for 15.5 min) to afford Form XXVIIatorvastatin calcium. Form XXVII atorvastatin calcium was obtained at148° C. and remained unchanged upon cooling to 35° C.

Form XXVIII Atorvastatin Calcium

A 0.3 g sample of amorphous atorvastatin calcium (U.S. Pat. No.6,087,511) was slurried with 1 mL of ethylene glycol at 50° C. for 24hours. The solids were isolated by vacuum filtration at ambientconditions to afford Form XXVIII atorvastatin calcium.

Form XXIX Atorvastatin Calcium

A 1.0 g sample of amorphous atorvastatin calcium (U.S. Pat. No.6,087,511) was slurried with 8 mL of water:tetrahydrofuran (4:1, v/v) atambient temperature. The mixture was seeded with atorvastatin calciumForm XII (U.S. Pat. No. 6,605,729) and stirred at ambient conditions for5 hours. The solids were isolated by vacuum filtration to afford FormXXIX atorvastatin calcium.

Form XXX Atorvastatin Calcium

Method A

A slurry containing 3.0 g of amorphous atorvastatin calcium (U.S. Pat.No. 6,087,511) and 24 mL of ethylene glycol was shaken on an ambienttemperature orbital shaker block for about 1 day. The slurry was vacuumfiltered and the solids were air dried at ambient temperature for 6 daysto afford Form XXX atorvastatin calcium.

Method B

A 200 mg sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was exposed to ACN vapor at ambient temperature inside a sealed chamberfor two months to afford Form XXX atorvastatin calcium.

The invention claimed is:
 1. A Form XXIX atorvastatin calcium having anX-ray powder diffraction containing the following 2θ values measuredusing CuK_(a) radiation: 8.0, 10.2, 11.5, 14.5, 15.3, 18.0, 19.6, 20.2,22.3, and 24.9.